This invention relates to a method of detecting the presence of bladder cancer in humans. More particularly, it relates to the discovery that if the ratio of C-reactive protein ("CRP") to total protein in urine is higher than the ratio of CRP to total protein in serum, this is indicative of bladder cancer and to a method for making this determination.
Bladder cancer ranks eleventh in cancer deaths in the United States. In general, the five year survival rate for people with low grade tumors is greater than 60 percent, while the five year survival rate for people with high grade and often metatastic tumors is less than 15 percent. Currently, the diagnosis and management of bladder cancer patients involves utilization of methods such as cystoscopy, urinary cytology, and the quantitation of normal and abnormal plasma related components in urine. Repeated cystoscopy involves patient discomfort, is costly, and may expose patients to certain surgical risks. Normal serum and plasma related components appear to have limited usefullness in the early diagnosis of bladder cancer as many of these same components are also present in increased concentrations in urine from patients with non-neoplastic disease.
The discovery of a substance in the urine of patients afflicted with bladder cancer which was associated with the cancer and indicative of its presence could provide a basis for a diagnostic test for the presence of bladder cancer. The development of a reliable and sensitive assay capable of detecting the presence of such a substance in urine would have many advantages over current methods of detecting bladder neoplasms. Since such a test would be non-invasive, it could be routinely employed to test urine from groups of high risk individuals such as those with occupational exposures to certain bladder carcinogens and other high risk groups. To verify the initial diagnosis of potential bladder cancer, further tests could be conducted.
Significant progress in the effort to detect and isolate such a tumor specific protein fraction has been made in the last ten years. Publications of interest in this area include: Detection of Bladder Cancer-Associated Antigens in Urine by Micro-Complement Fixation, J. J. Gozzo et al., Surg. Forum 25:117-119, 1974; Immunological Detection of Bladder Cancer Specific Antigen in Urine, J. J. Gozzo et al., Fed. Proc. 33:805, 1974; Immunological Detection of Human Bladder Carcinoma, A. P. Monaco et al., Annals of Surgery, 182:325-333, 1975; Immunological Detection and Partial Purification of Human Urinary Bladder Tumor Associated Antigens in Urine, W. Cronin et al., Fed. Proc. 34:1042, 1975; Partial Purification and Characterization of Urine Components from Patients with Bladder Cancer, W. Cronin et. al., Fed. Proc. 35:547, 1976; Immunological Detection of Human Bladder Carcinoma, A. P. Monaco et. al., Urology Digest, pages 31-32, April, 1976; Use of Heterogenous and Monospecific Antisera for the Diagnosis of Bladder Cancer, J. J. Gozzo et al., J. of Urology, 118:748-751, 1977; Qualitative Analysis of Tumor Related Components in Bladder Cancer Urines, P. O'Brien et al., Fed. Proc. 36:1327, 1977; Identification of Urinary Bladder Tumor Associated Antigens in Cancer Urine, W. Cronin et al., Fec. Proc. 36:1327, 1977; Identification of Tumor Antigens in Urine of Patients with Bladder Cancer, W. Cronin et al., Fed. Proc. 37:1486, 1978; Qualitative Analysis of Proteinuria Associated with Bladder Cancer, P. O'Brien et al., Invest. Urol., 17:28-32, 1979. This literature suggests that bladder cancer is associated with a number of nonspecific responses which are reflected in an elevation of normal protein components in the plasma or urine of cancer patients. Because these same components are also increased in other nonmalignant diseases, their use as tumor markers is not normally suitable. However, this literature also presents strong evidence that bladder tumor associated antigens do exist, and that it is possible that detection of such tumor associated antigens may be useful in the diagnosis of bladder cancer.
CRP is normally present in serum in low concentrations but elevated levels of CRP in serum are associated with certain diseases involving inflammation or tissue damage. As discussed in Acute Phase Reactants in Cancer, E. H. Cooper et al, Adv. Cancer Res., 30:1-44 (1979), various cancers can cause elevated CRP in serum. However, Mukin et al, in Determination of C-reactive Protein in the Urine of Patients with Pyretic Proteinuria, Zdravookhr Byeloruss, 7:23-24 (1966), found that unless patients are somewhat proteinuric, they do not excrete CRP in the urine even if the serum levels are elevated. No other studies have been reported where elevated urine CRP levels have measured and correlated with serum CRP levels.
Immunoassays involving tagged antibodies specific to various materials which behave as antigens in vivo are now widely available. The broad approach of these assays is to incubate a test sample suspected to contain the antigen with "tagged" antibody under conditions such that the detection of the antibody in the test vessel after incubation, as evidenced by detection of the tag, implies the presence of antigen in the sample. An immunoassay has now been developed for detection of CRP in urine and serum. Such an assay is a non-invasive, reliable screening test for bladder cancer detection. Since the first stage of detection proceeds by urinalysis, screening of at risk populations is practical. In view of the marked difference in survival rate in patients between early and late diagnosis of bladder cancer, the importance of such a development is manifest.